Although the overall trial showed no significant effect on breast cancer risk from estrogen replacement compared with placebo in women who no longer had a uterus, all low-risk subgroups showed significant reductions with unopposed estrogen ranging from 32% to 43%.

If validated, this would represent a new paradigm where estrogen-only HT is used for breast cancer prevention in selected women, Joseph Ragaz, MD, of the University of British Columbia School of Population and Public Health in Vancouver, said at a press conference here at the San Antonio Breast Cancer Symposium.

Estrogen was initially thought to be the culprit in the elevated breast cancer risk seen among women with an intact uterus in the parallel WHI study that showed a 26% excess in invasive breast cancer with the combination of estrogen and progestin.

"HT with estrogen alone may not be as unsafe as it was considered in the past," Ragaz told reporters.

However, his group's review and reanalysis of the WHI results drew strong criticism.

Many contacted by MedPage Today and ABC News worried that the researchers' enthusiasm might tempt overgeneralization.

"It will only cause confusion and it should not be highlighted," warned Judy E. Garber, MD, MPH, of the Dana-Farber Cancer Institute in Boston, and moderator of the press conference.

Women should not interpret these results as a sign it's safe to take estrogen with impunity outside the clinical trial setting, added Anthony Elias, MD, of the University of Colorado at Denver. "I have several serious reservations about this report."

WHI investigator Rowan Chlebowski, MD, PhD, of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, noted that these results have all been available in the published literature since publication of the results in 2006.

The researchers used the published results without access to the patient-level data for their poster presentation, pulling out the half of the subgroups that were positive to highlight, according to Chlebowski.

"It's not the appropriate way to [stimulate] changes in clinical behavior," he warned in an interview, "especially when you have a nonsignificant overall effect."

Ragaz's group pointed to four subgroups of women with significantly reduced breast cancer risk on estrogen alone versus placebo:

Those with a Gail risk score under 1.75, a group that represented 70.6% of women in the trial (HR 0.65, 95% CI 0.44 to 0.85)

Those who'd never been on HT -- slightly more than half of trial participants (HR 0.65, 95% CI 0.46 to 0.92)

Those with no prior history of breast disease, 71.5% of the sample (HR 0.57, 95% CI 0.41 to 0.78)

Those with no family history of breast cancer in a first degree relative (HR 0.68, 95% CI 0.50 to 0.92)

When results were stratified by age at start of HT in the trial, those 50 to 59 appeared to have the most favorable profile across the potential risks, such as coronary heart disease, colorectal cancer, venous thromboembolism, and total death, with the exception of hip fracture.

The investigators concluded that "in selected women under 60 years of age entering menopause, the HT based on estrogen alone could be safely incorporated into clinical guidelines."

However, "they're already in," Chlebowski told MedPage Today. "All the results have been integrated into the guidelines since 2006."

Ragaz suggested that the reason for the apparent benefit in this study compared with known negative effects that have led to the success of estrogen-blocking therapies like tamoxifen and the aromatase inhibitors may be a distinction between endogenous and exogenous estrogen.

But it may not be the difference between exogenous and endogenous estrogen as much as the time from menopause, Chlebowski countered.

His group's prior retrospective analyses of WHI data suggested that estrogen alone appeared protective only when started more than five years from surgically-induced menopause, he noted.

One hypothesis says that, after a period of estrogen deprivation, tumor cells that grew up in the low-estrogen environment can't adapt when estrogen is reintroduced, he noted.

"That is probably the case, and that would mean the estrogen isn't different," he told MedPage Today in an interview.

Elias added that the basis for a biologic difference between endogenous and exogenous estrogen isn't clear "since it all interconverts and achieves steady state in the woman."

Another concern was the duration of follow-up, noted Walter Willett, MD, MPH, DrPH, of Harvard School of Public Health.

"This new report needs to include the very important qualification that it only addressed relatively short-term use, and other studies have shown increased risk with longer-term use," he said in an e-mail to MedPage Today and ABC News.

The WHI investigators are in the process of publishing an additional five years of follow-up of the estrogen-only trial, which would bring the total to more than 12 years, according to Chlebowski.

"Those findings should inform practice," he told MedPage Today, suggesting that physicians wait for that data before considering a change of mind on estrogen replacement therapy.

This article was developed in collaboration with ABC News.

The WHI program is funded by the National Heart, Lung, and Blood Institute.

Ragaz and Garber reported having no conflicts of interest to disclose.

Chlebowski has reported that he has received consulting fees from AstraZeneca, Novartis, and Pfizer, lecture fees from AstraZeneca and Novartis, and grant funding from Amgen. His co-authors reported relationships with Procter & Gamble, Wyeth Laboratories, Upsher-Smith Laboratories, Wyeth Pharmaceuticals, Meditrina Pharmaceuticals, Merck, Boehringer Ingelheim, and Organon.